From antibody-drug conjugates and RNA, to CRISPR and CAR-T therapy, DDW asked the drug discovery industry what the most important development in oncology over the last five years has been.
As the US National Cancer Research Month draws to a close, we asked experts from across the industry “What do you feel has been the most exciting development in cancer research in the last five years?” Here are their answers.
Erin Goodhue, Director of Clinical Research and Development, and Dawn Faller, Senior Manager, Global Clinical Marketing, Therapeutic Systems, Terumo Blood and Cell Technologies:
“When thinking about cancer, breast cancer has surpassed lung cancer as the most diagnosed cancer worldwide with one in eight women diagnosed in their lifetime. Triple negative breast cancer (TNBC) is the most aggressive of breast cancers, accounting for approximately 15% of all breast cancers, and is exceedingly difficult to treat. Each year there are over two million newly diagnosed breast cancer patients worldwide.
We believe one of the most exciting developments that has high potential to make a significant difference to treating cancer is the novel treatment option to TNBC patients called Immunopheresis. Immunopheresis is a ‘subtractive therapy,’ in contrast to alternative drugs that constitute ‘additive’ therapies. Subtractive therapy is so exciting because it is designed to avoid the side effects, toxicity, and negative impact on a patient’s quality of life that are typical of other cancer treatments. This approach combines a plasma-filtration column with a therapeutic apheresis, cell processing and cell collection platform to extract specific immune-suppressive cytokines from patient plasma that are produced by solid cancer tumours like TNBC. These targeted cytokines are selectively removed with the intention of neutralising the cancer’s ability to block a patient’s natural immune defence mechanisms, which are significantly compromised in late-stage, metastatic disease. This potentially re-energises the immune system to fight cancers.”
Dr Jean-Nicolas Schickel, Director Cancer Immunotherapy, Vector BioPharma:
“I think that the most exciting development in oncology over the past years is the realisation that combination therapies represent the future of cancer care. Combining standard of care modalities such as chemotherapy or radiotherapy with immune checkpoints inhibitors (ICIs) has put back immunotherapies firmly in the forefront of the fight against cancer. ICIs when given alone have occasionally shown poor efficacy in some indications, and in patient subpopulations with immune-excluded or immune-cold tumours. Combining multiple ICIs has shown improved efficacy, exemplified by the approval of Nivolumab plus Ipilimumab combination in MSI-high colorectal cancer in 2018. Despite this approval, the outcome for patients receiving the combination remained marginal. Very recent data from Moderna’s and BioNTech’s personalised vaccines in combination with ICIs in melanoma and pancreatic cancer respectively have shown dramatic improvements when given as part of a triple combination (vaccine plus ICI and chemo/radiotherapy).
I strongly believe that the next frontier to further improve patient outcomes will be to favour an immune-prone tumour microenvironment (TME). This holds the promise to broaden the application of combination therapies to non-responsive patients. However, current TME remodelling therapies such as engineered cytokines or immune cell agonists usually come with strong sides effects, which reduces therapeutic index. A precise and safe delivery system which enables local activation and/or reinvigoration of immune cells at the site of action is urgently required to finally realise the full potential of TME remodelling agents.”
Dr Neil Torbett, CEO, PhoreMost:
“The past five years has seen tremendous progress across many areas of cancer research; from next generation antibody-drug conjugates (ADCs), to targeted therapeutics against historically hard to drug targets.
At PhoreMost, we have been particularly excited about the emergence of targeted protein degradation (TPD) as a new therapeutic modality. The concept of harnessing the ubiquitin-proteosome system to ‘destroy’ or degrade disease causing proteins has been established for some time. However, over the last five years the field has rapidly advanced, in large part due to the promising clinical progression of degrader therapeutics against multiple cancer targets. This has led to an explosion of activity across pharma and biotech to progress degrader therapeutics against an array of novel targets, which may ultimately transform treatment options for both cancer and many other diseases.
Whilst first generation degrader therapeutics have predominantly harnessed a single E3 ligase to mediate protein degradation (cereblon), at PhoreMost we are focussed on unlocking other E3 ligases of which there are over 600! We are even more excited about what the next five years will bring by way of new treatment options for cancer patients.”
Dr Fiona McLaughlin, Chief Scientific Officer of Avacta’s Therapeutics Division:
“Precision oncology continues to go from strength to strength as we find new ways of tailoring therapy. The field of Theranostics, a combination of diagnostics and therapeutics, has grown exponentially in the last few years. Theranostics is bringing together a specific radioactive agent which diagnoses a disease, with a second radioactive agent as treatment. This allows careful selection of specific patients that are more likely to respond to therapy, sparing patients who are less likely to respond. The PSMA targeted radiopharmaceutical Pluvicto from Novartis was the first radioligand therapy to be approved for PSMA-positive prostate cancer patients in March 2022. The protease fibroblast activation protein alpha (FAP-α) is another attractive theranostic target as it is highly expressed on cancer-associated fibroblasts and certain mesenchymal-derived tumour cells, and is expressed on up to 90% of cells in the tumour microenvironment.
FAPi PET is being developed as a highly sensitive imaging agent and can be used as a predictive biomarker for FAP targeted therapeutics, several of which are currently in clinical development. We expect this field to grow significantly in the coming years as these and other earlier stage assets are developed. The radiopharmaceutical market is expected to grow to $12 billion by 2030 and there is a substantial opportunity to grow much faster if safety and tolerability of these effective treatments can be improved.”
Billy Boyle, co-founder and CEO, Owlstone Medical:
“Some of the most exciting developments in cancer research have been the advancement of potential biomarkers within screening programmes for early detection. As well as better treatments, we are in desperate need of ways to detect cancer earlier when the chances of treatment being effective are dramatically higher. This approach is reliant on the uptake of the screening tests in the population, however, the more the invasive test, the lower the uptake.
Breath analysis be utilised is to introduce certain compounds into the body to explore how they are absorbed, metabolised, or excreted in exhaled breath – probing tumour-specific pathways and offering a readout of altered metabolism by enzymes associated with cancer. This could revolutionise screening programs to detect cancer earlier, meaning that patients can get onto relevant treatment pathways early, ultimately saving lives.”
Dr Vibhor Gupta, CEO and Founder of Pangaea:
“Cancer cachexia affects 40-80% of cancer patients and is attributed to 20-30% of cancer mortalities. Unfortunately, this complication remains exceedingly underdiagnosed, with up to 50% of cases being missed. This is due in part to poor screening practices and unclear clinical guidance. Early detection and intervention are essential, as cancer cachexia reduces treatment tolerance, increases treatment-related toxicity, and lowers response rates. In the UK, it is estimated that financial overhead from this complication could be as high as $1.5 billion.
Clinicians have tried to address this through manual review of patient records, but that is not a scalable solution given that it takes 40 minutes – 1 hour per patient. Technology teams have also tried addressing this using natural language processing (NLP) approaches, which look for a pre-empted set of clinical features (symptoms) based on existing medical knowledge. Given that such features can be common across several other conditions, the precision of such approaches is low and not applicable in the real world, especially given the heterogeneity of patient data.
One solution addresses these challenges by applying artificial intelligence (AI) and medical science, improving outcomes for cachectic cancer patients and reducing the burden on healthcare systems by enabling clinicians to discover six times more undiagnosed, misdiagnosed and miscoded patients who would have previously been missed through ICD-based searches or natural language processing (NLP) based approaches.”
Dr Michelle Fraser, Business Unit Manager, Base Editing at Revvity:
“It is widely appreciated that tumours are made up of heterogeneous populations of genetically diverse cells. Oncogenic driver mutations provide immortality to dividing cells, allowing them to accumulate mutations without the consequence of programmed cell death. This understanding of tumour diversity is driving a new approach to personalised therapy. By analysing the diverse cell populations of a tumour, it is possible to predict drug responsiveness and personalise a treatment strategy to minimise the outgrowth of resistant subpopulations. The intersection of cell, protein, RNA and DNA analysis at the single cell level has advanced significantly over the last five years and is particularly informative to our understanding of cancer biology and drug responsiveness.
On the drug screening side, the rapid rise of gene modulation and knock-out using CRISPR and RNA interference is giving us unparalleled insight into the function of drug candidates. Functional genomic screens provide insight into genetic pathways, cellular processes, novel therapeutic targets, and mechanisms of action of existing or potential therapeutics. Being able to monitor the effect of a drug on a live cell population that has been specifically genetically or transcriptionally modified in proteins that the drugs may interact with gives cancer researchers and drug developers the ability to understand the function of the drug.
One of the most exciting recent developments is the use of gene editing tools to create cell and gene therapies. For example, by editing T-cells derived from a patient or a donor to have them target the cancer cells specifically, these CAR-T therapies are engaging the patient’s own immune response to attack the cancer and cure the disease.”